Instituto de Biofísica Carlos Chagas Filho, CCS-Bloco G-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, 21949-900, Brazil.
Endocrinology. 2013 Mar;154(3):1361-72. doi: 10.1210/en.2012-1930. Epub 2013 Feb 13.
Diabetes mellitus (DM) disrupts the pituitary-thyroid axis and leads to a higher prevalence of thyroid disease. However, the role of reactive oxygen species in DM thyroid disease pathogenesis is unknown. Dual oxidases (DUOX) is responsible for H(2)O(2) production, which is a cosubstrate for thyroperoxidase, but the accumulation of H(2)O(2) also causes cellular deleterious effects. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is another member of the nicotinamide adenine dinucleotide phosphate oxidase family expressed in the thyroid. Therefore, we aimed to evaluate the thyroid DUOX activity and expression in DM rats in addition to NOX4 expression. In the thyroids of the DM rats, we found increased H(2)O(2) generation due to higher DUOX protein content and DUOX1, DUOX2, and NOX4 mRNA expressions. In rat thyroid PCCL3 cells, both TSH and insulin decreased DUOX activity and DUOX1 mRNA levels, an effect partially reversed by protein kinase A inhibition. Most antioxidant enzymes remained unchanged or decreased in the thyroid of DM rats, whereas only glutathione peroxidase 3 was increased. DUOX1 and NOX4 expression and H(2)O(2) production were significantly higher in cells cultivated with high glucose, which was reversed by protein kinase C inhibition. We conclude that thyroid reactive oxygen species is elevated in experimental rat DM, which is a consequence of low-serum TSH and insulin but is also related to hyperglycemia per se.
糖尿病（DM）会扰乱垂体-甲状腺轴，并导致甲状腺疾病的患病率增加。然而，活性氧在 DM 甲状腺疾病发病机制中的作用尚不清楚。双氧化酶（DUOX）负责 H2O2 的产生，H2O2 是甲状腺过氧化物酶的辅助底物，但 H2O2 的积累也会导致细胞有害影响。烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（NOX4）是另一种在甲状腺中表达的烟酰胺腺嘌呤二核苷酸磷酸氧化酶家族成员。因此，我们旨在评估 DM 大鼠的甲状腺 DUOX 活性和表达，以及 NOX4 表达。在 DM 大鼠的甲状腺中，我们发现由于 DUOX 蛋白含量和 DUOX1、DUOX2 和 NOX4 mRNA 表达增加，导致 H2O2 生成增加。在大鼠甲状腺 PCCL3 细胞中，TSH 和胰岛素均降低 DUOX 活性和 DUOX1 mRNA 水平，该作用可部分被蛋白激酶 A 抑制所逆转。DM 大鼠甲状腺中的大多数抗氧化酶不变或减少，而只有谷胱甘肽过氧化物酶 3 增加。在高葡萄糖培养的细胞中，DUOX1 和 NOX4 表达和 H2O2 生成显著增加，而蛋白激酶 C 抑制可逆转这种情况。我们得出结论，实验性大鼠 DM 中的甲状腺活性氧增加，这是低血清 TSH 和胰岛素的结果，但也与高血糖本身有关。
